Abstract Cells adjust lipid desaturation and membrane fluidity to maintain homeostasis in response to temperature shifts. This fundamental process occurs in nearly all forms of life, but its underlying mechanism in eukaryotes is largely unknown. From a C. elegans screen exploring how genes control sensitivity to oxygen, we discovered a novel pathway comprising the genes egl-25 and acdh-11 (acyl-CoA dehydrogenase, ACDH) that facilitates temperature adaptation via the stearoyl-CoA desaturase (SCD) FAT-7 (unpublished). egl-25 encodes a C. elegans homolog of the mammalian receptors for adiponectin, which has potent insulin-sensitizing, anti- oxidative and anti-inflammatory properties in mammals. Human ACDH deficiency causes the most common inherited disorders of fatty acid oxidation, with syndromes that are exacerbated by hyperthermia, analogous to the vulnerability of C. elegans acdh-11 mutants to heat. SCDs control membrane fluidity by catalyzing the limiting step of fatty acid desaturation, and their dysregulation causes metabolic disorders and cancer. The goals of this project are to leverage our preliminary findings, innovative bioassays and powerful genetic approaches in C. elegans to molecularly identify mutations defining new genes interacting with egl-25/acdh-11 (Aim I), to characterize the functional roles of egl-25/acdh-11 in controlling fatty acid metabolism, desaturation and signaling (Aim II), and to elucidate the similarity and mechanisms of action of key egl-25/acdh-11 pathway components that are conserved in C. elegans and human cells (Aim III). This new investigator?s prior training experience and areas of expertise in C. elegans genetic screens and mammalian cell signaling are well suited for carrying out this project in the Cardiovascular Research Institute at the University of California, San Francisco (UCSF). This proposal has the potential for high impact because it should 1) reveal a novel conserved pathway that drives temperature adaptation via a new mode of fatty acid signaling and suggests a mechanistic basis of the thermo-sensitivity phenotype caused by ACDH deficiency, and 2) elucidate mechanisms and regulators of the egl-25/acdh-11 pathway that should provide novel therapeutic targets for treating human conditions including metabolic and vascular inflammatory disorders.